Comorbid mood and anxiety disorders are a frequent occurrence in psychiatric populations. The clinical course of depression and response to treatment of depression is worse in the presence of a comorbid anxiety disorder. Our previous data using a stressor to activate the HPA axis, demonstrated that ACTH stress reactivity was increased in subjects with comorbid major depression and social anxiety disorder (SAD) compared to normal subjects, and pure major depression (MDD). Studies of women with childhood abuse and MDD found a similar exaggerated response to the same stressor, the TSST. These data suggest that early onset anxiety disorders and trauma may show similar increased stress reactivity. Studies by others suggest that early trauma and MDD leads to increased sensitivity to dexamethasone, the opposite of what is observed in traditional depressed patients. In this proposal we will evaluate whether increased reactivity of the HPA axis to the TSST in comorbid mood and anxiety disorders is also accompanied by increased basal activity, as assessed by the ACTH response to metyrapone, a purely "endocrine" challenge. In addition we will evaluate the response to dexamethasone negative feedback in the same subjects to determine if increased stress reactivity is linked to failure of the inhibitory systems or whether these two phenomena are independent. We will examine if timing of trauma (adult vs. childhood) to determine if different patterns of HPA axis dysregulation are observed in patients with PTSD and MDD dependent upon the time of trauma exposure. We will also examine the specificity of trauma by comparing the results in the comorbid MDD plus PTSD groups to a comorbid MDD plus early onset SAD group. We hypothesize that all comorbid anxiety disorders will lead to exaggerated stress response to the TSST but that MDD with early trauma or early onset SAD will show normal PM drive (as assessed by metyrapone) and exaggerated feedback to dexamethasone. We further hypothesize that MDD with PTSD secondary to adult trauma only will show increased basal drive and decreased negative feedback to dexamethasone, the classic MDD pattern. Finally, we hypothesize that pure MDD will show increased metyrapone response, insensitivity to dexamethasone and a normal response to the TTST. These data will further our understanding of the effects and timing of trauma on the HPA axis stress reactivity and feedback. Exposure to one type of stressor, a trauma, can lead to PTSD but controversy still exists as to whether there are any characteristic stress hormone changes with PTSD. PUBLIC HEALTH RELEVANCE: This proposal will explore if timing of first trauma, i.e. childhood versus adult, leads to different consequences on basal secretion of stress hormones in the evening and to changes in feedback sensitivity to dexamethasone, a synthetic compound similar to cortisol. We will also explore if timing of trauma changes the stress hormone response to a public speaking challenge. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]